Sofosbuvir in crystalline form and process for its preparation

ABSTRACT

Sofosbuvir in crystalline Form α, process for its production and use in pharmaceutical compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.15/308,253, filed on Nov. 1, 2016, which in turn is a 371 ofPCT/EP2015/067422 filed Jul. 29, 2015, which claims the benefit ofItalian Patent Application No. M102014A001411, filed Aug. 1, 2014; thecontents of each of which are incorporated herein by reference.

FIELD OF INVENTION

The present invention relates to a stable polymorphic form of Sofosbuvirand a method for its preparation.

BACKGROUND OF THE INVENTION

Sofosbuvir is a prodrug used for the treatment of hepatitis C.

Hepatitis C is an infectious disease caused by Hepatitis C virus (HCV)which affects primarily the liver. The infection is often asymptomaticbut its chronic infection can lead to the scarring of the liver andfinally to cirrhosis, which is generally apparent after many years. Insome cases the liver cirrhosis can develop liver failure, liver cancer,esophageal and gastric varices. HCV is transmitted primarily by directcontact with infected blood, often caused by intravenous drug use,poorly sterilized equipment and blood transfusions.

Hepatitis C virus causes a chronic infection in 50-80% of the peopleswho are infected with, among them about 40-80% is treated. In general,the pharmacological treatment is recommended in patients with liverchanges caused by virus; the reference treatment is a combination ofpegylated interferon alpha and ribavirin to be taken for a period of 24or 48 weeks, depending on the HCV virus genotype. It is observed thatthis treatment leads to improvements in 50-60% of cases. In phenotypeswhich are more difficult to be treated these two drugs are used incombination with boceprevir and telaprevir bringing the cure rate from40% to 70%. The side effects of the treatment are frequent: halfpatients have flu like symptoms and one third has emotional problems,moreover the treatment carried out during the first six months is moreeffective than once hepatitis C has become chronic.

Sofosbuvir is a drug for the treatment of hepatitis C, approved at thebeginning of the year by EMA, it is taken orally and acts with a directmechanism of action on the life cycle of the virus abolishing itsreplication as being a prodrug inhibitor pan-genotype of RNA polymeraseNS5B RNA-dependent of HCV, it can be incorporated into HCV RNA NS5Bpolymerase and acts as a chain terminator.

Sofosbuvir has moreover shown a reduced number of complications of theliver disease and a reduced number of adverse effects than patientsundergoing other treatments.

Sofosbuvir is a compound of formula (I)

chemically known as isopropyl(2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidine-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]-aminopropanoate,marketed as Sovaldi® and described in U.S. Pat. No. 8,563,530.

Some polymorphic forms of Sofosbuvir are known in the literature.

U.S. Pat. No. 8,618,076 describes crystalline, hydrated and solvatedforms of Sofosbuvir, named as Form I (crystalline), Form 2(crystalline), Form 3 (chloroform solvate), Form 4 (hydrate), Form 5(crystalline) and Form 6 (crystalline) and describes also two amorphousforms.

Polyphormism is the property of the molecules to assume more than onecrystalline or amorphous form in their solid state. Some substances areknow to exist in only one crystalline or amorphous form; others indeedcan have two or more crystalline forms. Polymorphs are different solidswith the same molecular formula but with different physical propertiesthat can be advantageous or disadvantageous compared with the otherpolymorphic forms of the same family.

The morphology of organo-chemical active ingredients is important fortheir pharmaco chemical development. A crystalline form, compared toother crystalline forms, can have many advantages. A suitable processfor a crystalline form can give to active ingredient's manufacturersseveral advantages, such as, the use of steps or solvents cheap or witha low environmental impact, higher yields and higher purity of thedesired product.

The polymorphism, the number of crystalline forms of an organo-chemicalcompound, their stability and their behavior in a living organism arenever predictable. The different polymorphs of a compound have differentenergies of the crystal lattice and show in this way, different physicalproperties of the solid state (such as shape, density, melting point,colour, stability, dissolution rate, ease of grinding, granulationetc.). In polymorphism, these morphological differences can have drasticeffects on the flowability of the ground solid (the flowability regardsthe easiness whereby the material is treated during the processing intoa pharmaceutical product), on shipping and storage stability ofdifferent forms of administration, on the ability to produce differentforms of administration, on solubility in polar or non polar, protic oraprotic solvents, on solubility in aqueous solutions, on solubility ingastric juices, on blood solubility and finally on bioavailability.

The dissolution rate of an active ingredient in the gastric fluid of apatient can have therapeutical effects because it determines the maximumconcentration that an active ingredient can reach in the blood by oraladministration. Other important properties of polymorphic forms affectthe easiness of transforming the active ingredient form inpharmaceutical dosages, on the flowability of a powder or a granulateform and the surface properties that determine if the crystals of theform will stick each other once compressed in a tablet.

A polymorphic form can have a different thermic behavior compared to anamorphous form or any other polymorphic form. Thermic behavior can bemeasured in laboratory through techniques such as capillary meltingpoint and differential scanning calorimetry (DSC) and can be used todistinguish various polymorphic forms. A polymorphic form can havedifferent spectroscopical properties that can be detected trough theX-Ray Powder diffraction (XRPD).

The discovery of new polymorphic forms of a pharmaceutical compoundgives another possibility to improve the characteristics of saidproduct. An expert of pharmaceutical techniques extends his/herknowledge of forms useful for the development of a pharmaceutical formwith a targeted release profile or with other characteristics such asfluidity and dissolution rate in aqueous liquids.

SUMMARY OF THE INVENTION

The aim of the present invention is to give a new stable and nothygroscopic crystalline form which can be prepared with an ease,repeatable method with excellent yields and easy industrialapplicability.

We have now found a stable and not hygroscopic crystalline form ofSofosbuvir suitable for the preparation of stable pharmaceuticalformulations as obtainable with a distribution of the particle sizessuch to allow a good compressibility and flowability.

It is therefore object of the present invention a crystalline form ofSofosbuvir, from now on named also as Form α, characterized by an XRPDcomprising peaks at about 7.96; 10.28; 12.32; 16.64; 17.00; 18.56;19.28; 19.88; 20.72; 21.88; 23.08; 24.24; 25.16; 27.00; 27.96±0.2° 2θaccording to FIG. 1.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: XRPD of Sofosbuvir Form α.

The new polymorphic form is also characterized by a distribution of theparticles sizes (PSD) where the size of the 90% of the particles is from10 to 50 μm and by the following parameters:

Bulk Density 0.22 g/ml Tapped Density 0.29 g/ml Compressibility index24.4 Hausner ratio 1.32

It is a further object of the present invention a process for thepreparation of Sofosbuvir in crystalline Form α which comprises a stepof dissolution of Sofosbuvir in ketones and a crystallization step ofthe solution obtained by said dissolution.

The ketones used for the process object of the present invention areselected among the group consisting of acetone, metyl ethyl ketone,isobutyl methyl ketone and diethyl ketone: the ketones are preferablyselected among the group consisting of metyl ethyl ketone and isobutylmethyl ketone.

Preferably, said crystallization step is obtained by cooling of thesolution or by a slow solvent evaporation.

According to a preferred embodiment, the process of the presentinvention comprises the following steps:

i. dissolution of Sofosbuvir in isobutyl methyl ketone at a temperaturewithin the range of 50-60° C.;

ii. cooling of the solution obtained from step i. to a temperature of20° C. under stirring till the precipitation of the product;

iii. separation by filtration of the product obtained from step ii;

iv. under vacuum drying of the product obtained from step iii.

DETAILED DESCRIPTION OF THE INVENTION

The process for the preparation of Sofosbuvir Form α according to thepresent invention is particularly simple and of easy industrialapplicability.

Therefore, further objects of the present invention are the use ofSofosbuvir Form α as a medicament and pharmaceutical compositionscontaining it as an active ingredient in mixture with a suitablecarrier.

All the terms used in the present application, unless otherwiseindicated, are to be understood in their common meaning as known in theart. The term “about” comprises the usual experimental error of anymeasurement.

Although the present invention has been described in its characterizingfeatures, their equivalents and modifications obvious to the skilled inthe art are included in the present invention.

The present invention will be now illustrated through some exampleswithout limiting it.

EXAMPLES

Diffraction spectra XRPD were carried out through a diffractometer APD2000 Ital Structures at ambience temperature using a tube CuKa (40 Kv,30 Ma) as X ray source. The data were collected through a 2q continuousscan at a scan speed of 0.02°/s in the range of 3°-40° in 2q.

Example 1

5 g of Sofosbuvir were suspended in 15 ml of isobutyl methyl ketone intoa reaction flask under stirring, the temperature was kept at about50/60° C. and the mixture was kept under such conditions until completedissolution. The temperature was brought to about 20° C. and the mixturewas kept under stirring for about one hour. The resultant solid wasfiltered and washed with isobutyl methyl ketone (2×5 ml) at thetemperature of 20° C. and dried in oven under vacuum at 45-50° C. togive 4.5 g of Sofosbuvir Form α.

PSD=d(0.1):1.831 μm;

-   -   d(0.5):5.263 μm;    -   d(0.9):20.369 μm.

Example 2

5 g of Sofosbuvir were suspended in 15 ml of methyl ethyl ketone into areaction flask under stirring, the temperature was brought to about50-60° C., the reaction mixture was kept under such conditions untilcomplete dissolution and the resultant solution was transferred into acrystallizer. The solvent was evaporated at room temperature to give 5 gof Sofosbuvir Form α.

Example 3

5 g of Sofosbuvir were suspended in 15 ml of acetone into a reactionflask under stirring, the temperature was brought to about 50-60° C.,the reaction mixture was kept under such conditions until completedissolution and the resultant solution was transferred into acrystallizer. The solvent was evaporated at room temperature to give 5 gof Sofosbuvir Form α.

1. Sofosbuvir in crystalline Form α characterized by an XRPD comprisingthe following peaks: 7.96; 10.28; 12.32; 16.64; 18.56; 19.28; 19.88;20.72; 21.88; 23.08; 24.24; 25.16; 27.00; 27.96±0.2° 2θ.
 2. A processfor the preparation of Sofosbuvir according to claim 1 wherein itcomprises a step of dissolution of Sofosbuvir in ketones and acrystallization step of the solution obtained by said dissolution. 3.The process according to claim 2, wherein said ketones are selected fromthe group consisting of acetone, methyl ethyl ketone, isobutyl methylketone and diethyl ketone.
 4. The process according to claim 2, whereinsaid ketones are selected from the group consisting of methyl ethylketone and isobutyl methyl ketone.
 5. The process according to claim 2,wherein said crystallization is obtained by cooling or by solventevaporation.
 6. The process according to claim 2 wherein it comprises:i. dissolution of Sofosbuvir in isobutyl methyl ketone at a temperaturewhithin the range of 50-60° C.; ii. cooling the solution obtained fromstep i to a temperature of 20° C. till the precipitation of the product;iii. filtration of the product obtained from step ii.; and iv. undervacuum drying of the product obtained from step iii.
 7. A pharmaceuticalcomposition comprising Sofosbuvir according to claim
 1. 8. The processaccording to claim 2, wherein said Sofosbuvir obtained with said processhas a PSD wherein the size of the 90% of the particles is in the rangeof 10-50 μm.
 9. The process according to claim 2, wherein saidSofosbuvir obtained with said process has the following PSD: d(0.1):1.831 μm; d(0.5): 5.263 μm; d(0.9): 20.369 μm.